Processes for the facile synthesis of diaryl amines and analogues thereof

ABSTRACT

The present invention relates to processes for the facile synthesis of diaryl amines and analogues thereof. The processes of the present invention produce diaryl amines in high yield and purity. The present invention also relates to intermediates useful in the process of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. provisionalapplication Ser. No. 60/446,641, filed Feb. 10, 2003, and U.S.provisional application Ser. No. 60/474,272, filed May 28, 2003, theentire contents whereof is incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to processes for the facile synthesis ofdiaryl amines and analogues thereof. The processes of the presentinvention produce diaryl amines in high yield and purity. The presentinvention also relates to intermediates useful in the process of thepresent invention. The present invention also relates to a diaryl aminesproduced by the processes of the present invention.

BACKGROUND OF THE INVENTION

Protein kinases are involved in various cellular responses toextracellular signals. Recently, a family of mitogen-activated proteinkinases (MAPK) has been discovered. Members of this family are Ser/Thrkinases that activate their substrates by phosphorylation [B. Stein etal., Ann. Rep. Med. Chem., 31, pp. 289–98 (1996)]. MAPKs are themselvesactivated by a variety of signals including growth factors, cytokines,UV radiation, and stress-inducing agents.

One particularly interesting MAPK is p38. p38, also known as cytokinesuppressive anti-inflammatory drug binding protein (CSBP) and RK, wasisolated from murine pre-B cells that were transfected with thelipopolysaccharide (LPS) receptor, CD14, and induced with LPS. p38 hassince been isolated and sequenced, as has the cDNA encoding it in humansand mice. Activation of p38 has been observed in cells stimulated bystress, such as treatment of lipopolysaccharides (LPS), UV, anisomycin,or osmotic shock, and by cytokines, such as IL-1 and TNF.

Inhibition of p38 kinase leads to a blockade on the production of bothIL-1 and TNF. IL-1 and TNF stimulate the production of otherproinflammatory cytokines such as IL-6 and IL-8 and have been implicatedin acute and chronic inflammatory diseases and in post-menopausalosteoporosis [R. B. Kimble et al., Endocrinol., 136, pp. 3054–61(1995)].

Based upon this finding, it is believed that p38, along with otherMAPKs, have a role in mediating cellular response to inflammatorystimuli, such as leukocyte accumulation, macrophage/monocyte activation,tissue resorption, fever, acute phase responses and neutrophilia. Inaddition, MAPKs, such as p38, have been implicated in cancer,thrombin-induced platelet aggregation, immunodeficiency disorders,autoimmune disease, cell death, allergies, osteoporosis andneurodegenerative diseases. Inhibitors of p38 have also been implicatedin the area of pain management through inhibition of prostaglandinendoperoxide synthase-2 induction. Other disease associated with IL-1,IL-6, IL-8 or TNF overproduction are set forth in WO 96/21654.

Many molecules possessing medicinally important properties againstvarious targets, including MAPKs, comprise diaryl amines. One example ofthis is a class of molecules identified as potent p38 MAP kinaseinhibitors (see, e.g., WO 99/58502 and WO 00/17175). However, althoughthey are effective as drugs, there are few ways to make arylamine-containing molecules without a significant amount of by-product.Palladium-catalyzed couplings of an aryl amine and aryl halide have beenthe traditional strategy to produce a molecule comprising a diarylamine. However, problems with over-addition of the aryl halide partnerto the amine have traditionally resulted in low yields and purities whena primary aryl amine is employed. For this reason, primary amines arenot commonly employed substrates for this transformation, which haslimited the scope of the palladium-catalyzed coupling reaction.

Accordingly, the need exists for a process for the facile synthesis ofdiaryl amines and analogues thereof that avoids the problem ofover-arylation, to obtain diaryl amines in high yield and purity. Therealso exists a need for intermediates produced by such a process.

SUMMARY OF THE INVENTION

According to one embodiment, the present invention provides processesfor the facile synthesis of diaryl amines that avoid the problem ofover-arylation, are amenable to large scale preparation, and providehigh yields. The present invention also avoids the use of harmfulreagents such as tin compounds. Specifically, the present inventionprovides a process wherein a primary aryl amine is rendered temporarily“secondary” by adding a suitable protecting group to the nitrogen. Onceformed, this protected aniline derivative undergoes an alkali metalsalt-promoted or transition metal-catalyzed cross coupling with an arylleaving group to produce an intermediate, which, upon deprotection,produces the diaryl amine substrate. The product may be produced withfew by-products and in high yield.

The invention provides processes for producing a compound of the formula(I):

or a salt thereof,wherein:

Ar₁ and Ar₂ are as defined below.

The processes of this invention comprise the step of coupling a compoundof formula (II) with an amine of formula (III) to obtain a diaryl amineof formula (I), in the presence of an alkali metal salt or transitionmetal catalyst:Ar₁—X  (II)Ar₂—NH—Y  (III)wherein:

Ar₁, Ar₂, X, and Y are as defined below.

The processes of this invention have the advantages of allowingpreparation of a compound of formula (I) from a primary aryl aminederivative without the problem of over-arylation. The processes of thisinvention have the further advantage of allowing preparation of acompound of formula (I) in high yield and purity, in addition to facilereaction conditions that are readily scaled up for large scalepreparation.

DETAILED DESCRIPTION OF THE INVENTION

The present invention overcomes the difficulties and shortcomings of theprior art and provides processes for producing a compound of the formula(I):

or a salt thereof,wherein:

Ar₁ and Ar₂ are independently Q;

wherein each Q is an aryl or heteroaryl ring system optionally fused toa saturated or unsaturated 5–8 membered ring having 0–4 heteroatoms;

-   -   wherein Q is optionally substituted at one or more ring atoms        with one or more substituents independently selected from halo;        C₁–C₆ aliphatic optionally substituted with N(R′)₂, OR′, CO₂R′,        C(O)N(R′)₂, OC(O)N(R′)₂, NR′CO₂R′, NR′C(O)R′, SO₂N(R′)₂,        N═CH—N(R′)₂, or OPO₃H₂; C₁–C₆ alkoxy optionally substituted with        N(R′)₂, OR′, CO₂R′, C(O)N(R′)₂, OC(O)N(R′)₂, SO₂N(R′)₂,        NR′CO₂R′, NR′C(O)R′, N═CH—N(R′)₂, or OPO₃H₂; Ar₃; CF₃; OCF₃;        OR′; SR′; SO₂N(R′)₂; OSO₂R′; SCF₃; NO₂; CN; N(R′)₂; CO₂R′;        CO₂N(R′)₂; C(O)N(R′)₂; NR′C(O)R′; NR′CO₂R′; NR′C(O)C(O)R′;        NR′SO₂R′; OC(O)R′; NR′C(O)R²; NR′CO₂R²; NR′C(O)C(O)R²;        NR′C(O)N(R′)₂; OC(O)N(R′)₂; NR′SO₂R²; NR′R²; N(R²)₂; OC(O)R²;        OPO₃H₂; and N═CH—N(R′)₂;

R′ is selected from hydrogen; C₁–C₆ aliphatic; or a 5–6 memberedcarbocyclic or heterocyclic ring system optionally substituted with 1 to3 substituents independently selected from halo, C₁–C₆ alkoxy, cyano,nitro, amino, hydroxy, and C₁–C₆ aliphatic;

R² is a C₁–C₆ aliphatic optionally substituted with N(R′)₂, OR′, CO₂R′,C(O)N(R′)₂ or SO₂N(R′)₂; or a carbocyclic or heterocyclic ring systemoptionally substituted with N(R′)₂, OR′, CO₂R′, C(O)N(R′)₂ or SO₂N(R′)₂;

wherein Ar₃ is an aryl or heteroaryl ring system optionally fused to asaturated or unsaturated 5–8 membered ring having 0–4 heteroatoms;

wherein Ar₃ is optionally substituted at one or more ring atoms with oneor more substituents independently selected from halo; C₁–C₆ aliphaticoptionally substituted with N(R′)₂, OR′, CO₂R′, C(O)N(R′)₂, OC(O)N(R′)₂,NR′CO₂R′, NR′C(O)R′, SO₂N(R′)₂, N═CH—N(R′)₂, or OPO₃H₂; C₁–C₆ alkoxyoptionally substituted with N(R′)₂, OR′, CO₂R′, C(O)N(R′)₂, OC(O)N(R′)₂,SO₂N(R′)₂, NR′CO₂R′, NR′C(O)R′, N═CH—N(R′)₂, or OPO₃H₂; CF₃; OCF₃; OR′;SR′; SO₂N(R′)₂; OSO₂R′; SCF₃; NO₂; CN; N(R′)₂; CO₂R′; C₂N(R′)₂;C(O)N(R′)₂; NR′C(O)R′; NR′CO₂R′; NR′C(O)C(O)R′; NR′SO₂R′; OC(O)R′;NR′C(O)R²; NR′CO₂R′; NR′C(O)C(O)R²; NR′C(O)N(R′)₂; OC(O)N(R′)₂;NR′SO₂R²; NR′R²; N(R²)₂; OC(O)R²; OPO₃H₂; and N═CH—N(R′)₂.

In a preferred embodiment, Ar₁ and Ar₂ are independently selected fromoptionally substituted phenyl, naphthyl, benzimidazolyl, benzothienyl,benzofuranyl, indolyl, quinolinyl, benzothiazolyl, benzooxazolyl,benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzoisoxazolyl,pyridyl, pyrimidyl, pyridazinyl, tetrazolyl, furanyl, imidizaolyl,isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, thiazolyl, triazolyl, andthienyl. In a more preferred embodiment, Ar₁ and Ar₂ are independentlyselected from optionally substituted phenyl and pyridyl. In an even morepreferred embodiment, Ar₁ is optionally substituted pyridyl and Ar₂ isoptionally substituted phenyl.

The processes of this invention comprise the step of coupling a compoundof formula (II) with an amine of formula (III) to obtain a diaryl amineof formula (I), in the presence of an alkali metal salt or transitionmetal catalyst:Ar₁—X  (II)Ar₂—NH—Y  (III)wherein:

-   -   X is a leaving group; and    -   Y is —C(O)—O-Z; and    -   Z is selected from C₁–C₆ aliphatic, benzyl, Fmoc, —SO₂R′ and Q,        provided that Q is not substituted with X or alkyne; wherein        Ar₁, Ar₂, Q and R′ are as defined above.

Scheme 1 below depicts a preferred process of the present invention:

wherein Ar₁, Ar₂, X, and Y are as defined above. The steps illustratedabove may be described as follows:Step 1:

A compound of formula (II), bearing a suitable leaving group X, isreacted with a compound of formula (III), which bears the Y—NH-moiety.The reaction is conducted in the presence of an alkali metal salt, suchas cesium carbonate; or alternatively a transition metal catalyst, andoptionally a base and optionally one or more ligands.

In one embodiment, a transition metal catalyst is used. An exemplarytransition metal catalyst that can be used comprises a transition metalion or atom and one or more suitable ligands. Preferably, the transitionmetal catalyst comprises a Group 8 metal. More preferably, thetransition metal catalyst comprises palladium. According to a preferredembodiment, two different ligands are simultaneously used in step 1.

According to a preferred embodiment, a base is used in step 1 inconjunction with the transition metal catalyst. Suitable bases includeKOtBu, NaOtBu, K₃PO₄, Na₂CO₃, and Cs₂CO₃. More preferably, the base isK₃PO₄.

Preferred solvents for step 1 when using a transition metal catalystinclude toluene and non-polar aprotic solvents such as MTBE, DME, andhexane.

In another embodiment, an alkali metal salt is used in step 1.Preferably, the alkali metal salt is a cesium salt.

Preferred solvents for step 1 when using an alkali metal salt includepolar aprotic solvents such as NMP.

Step 2:

In step 2, radical Y of (IV) is removed to produce the diaryl amine offormula (I).

According to a preferred embodiment, an acid, such as TFA, HCl, HBr, orHI is used in step 2. More preferably, the acid is TFA.

Preferred solvents for step 2 include chlorinated solvents such asCH₂Cl₂, 1,2-dichloroethane, and chlorobenzene.

The processes of this invention have the advantages of allowingpreparation of a compound of formula (I) from a primary aryl aminederivative without the problem of over-arylation. The processes of thisinvention have the further advantage of allowing preparation of acompound of formula (I) in high yield and purity, and on a large scale.

Step 1 Reagents:

Transition metal catalysts suitable for the present invention comprise atransition metal atom or ion and one or more ligands. The transitionmetal may exist in any suitable oxidation state ranging from zerovalence to any higher valence available to the transition metal.According to a preferred embodiment, the transition metal catalystcomprises a Group 8 metal. More preferably, the transition metalcatalyst comprises palladium. Catalyst complexes may include chelatingligands, including, without limitation, alkyl and aryl derivatives ofphosphines and biphosphines, imines, arsines, and hybrids thereof.

More preferably, the transition metal catalyst is a palladium catalystof the formula PdL_(n), wherein each L is independently selected fromCl, —OAc, —O-tolyl, halogen, PPh₃, dppe, dppf, and BINAP; and n is aninteger from 1–4. The aforementioned transition metal catalysts may beprepared using methods known in the art.

A variety of ligand transformations may occur throughout the process ofthe present invention. The ligand may be bound to the transition metalthroughout the process of the present invention, or the ligand may be ina labile configuration in relation to the transition metal during all orpart of the process. Accordingly, the term “transition metal catalyst”as used herein includes any transition metal catalyst and/or catalystprecursor as it is introduced into the reaction vessel and which is, ifnecessary, converted in situ into the active form of catalyst thatparticipates in the reaction.

The quantity of the transition metal catalyst to be used in the presentprocess is any quantity that promotes the formation of the diaryl amineproduct. According to a preferred embodiment, the quantity is acatalytic amount, wherein the catalyst is used in an amount that is lessthan stoichiometric relative to the aryl components. In anotherpreferred embodiment, the catalyst is present in the range of about 0.01to about 20 mole percent relative to the non-amine aryl component, morepreferably about 1 to about 10 mole percent, and even more preferablyabout 1 to about 5 mole percent.

One of skill in the art may readily select an appropriate solvent to usein the process of the present invention. A solvent may be present in anyquantity need to facilitate the desired process, and does notnecessarily have to be a quantity to dissolve the substrates and/orreagents of the desired process. A solvent according to the presentinvention will not interfere with the formation of the diaryl amineproduct. Examples of suitable solvents include, without limitation,halogenated solvents, hydrocarbon solvents, ether solvents, proticsolvents, and aprotic solvents. Mixtures of solvents are also includedwithin the scope of this invention. Preferred solvents useful for Step 1of the process of the present invention using a transition metalcatalyst include toluene, benzene, or a non-polar aprotic solvent suchas MTBE, DME, or hexane.

According to one embodiment, the coupling step using a transition metalcatalyst (Step 1) occurs in the presence of a base. Examples of suitablebases include, without limitation, alkali metal hydroxides, alkali metalalkoxides, metal carbonates, phosphates, alkali metal aryl oxides,alkali metal amides, tertiary amines, (hydrocarbyl)ammonium hydroxides,and diaza organic bases. The quantity of base used may be any quantitywhich allows for the formation of the diaryl amine product. Preferredbases of the present invention include KOtBu, NaOtBu, K₃PO₄, Na₂CO₃, andCs₂CO₃.

Alkali metal salts suitable for the present invention comprise salts ofsodium, potassium, rubidium or cesium ions. Preferably, alkali metalsalts suitable for the present invention comprise salts of potassium orcesium ions. Preferred alkali metal salts comprise carbonate, phosphate,and alkoxide salts. More preferred alkali metal salts suitable includepotassium carbonate and cesium carbonate. Most preferably, the alkalimetal salt is cesium carbonate.

The quantity of the transition metal catalyst to be used in the presentprocess is any quantity that promotes the formation of the diaryl amineproduct.

Preferred solvents useful for Step 1 of the process of the presentinvention using an alkali metal salt include polar aprotic solvents suchas NMP.

Step 2 Reagents:

According to a preferred embodiment, the protecting group removal step(Step 2) occurs in the presence of an acid. Examples of suitable acidsinclude, without limitation, HCl, HBr, HI, and organic acids includingformic acid, acetic acid, propionic acid, butanoic acid, methanesulfonicacid, p-toluene sulfonic acid, benzenesulfonic acid, and trifluoroaceticacid. Preferred acids of the present invention include HCl, HBr, HI, andTFA.

Preferred solvents for Step 2 of the process of the present inventioninclude chlorinated solvents such as CH₂Cl₂, 1,2-dichloroethane, andchlorobenzene.

In one embodiment of the present invention, X is a leaving group.According to a preferred embodiment, X is selected from the groupconsisting of Cl, Br, I, F, OTf, OTs, iodonium, and diazo.

In one embodiment of the present invention, Y is a carbamate amineprotecting group. According to a preferred embodiment, Y is Boc.

As used herein, the following definitions shall apply unless otherwiseindicated. Also, combinations of substituents are permissible only ifsuch combinations result in stable compounds.

Some of the abbreviations used throughout the specification (includingthe chemical formulae) are:

-   Boc=t-butoxycarbonyl-   Fmoc=fluorenylmethoxycarbonyl-   Tf=trifluoromethanesulfonate-   Ts=p-toluenesulfonyl-   Ms=methanesulfonyl-   TFA=trifluoroacetic acid-   Ac=acetyl-   dba=trans,trans-dibenzylideneacetone-   dppe=1,2-bis-(diphenylphosphino)ethane-   dppf=1,1′-bis-(diphenylphosphanyl)ferrocene-   dppp=propane-1,3-diylbis(diphenylphosphane)-   BINAP=2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl-   MTBE=methyl t-butyl ether-   DME=dimethoxyethane-   CDI=1,1′-carbonyl-diimidazole-   DCC=N,N′-dicyclohexylcarbodiimide-   EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-   HOBt=N-hydroxybenzotriazole-   NMP=N-methylpyrrolidinone-   DMF=dimethylformamide-   MCPBA=m-chloroperbenzoic acid-   MMPP=magnesium monoperoxyphthalate hexahydrate-   DIBAL-H=diisobutyl aluminum hydride-   LAH=lithium aluminum hydride-   super hydride=lithium triethylborohydride-   L-selectride=lithium tri-sec-butylborohydride-   Red-Al=sodium bis(methoxyethoxy)aluminum hydride-   IPA=isopropanol-   glyme=dimethoxy ethane-   diglyme=bis(2-methoxy ethyl)ether

As used herein, the following definitions shall apply unless otherwiseindicated. The phrase “optionally substituted” is used interchangeablywith the phrase “substituted or unsubstituted.” Also, combinations ofsubstituents are permissible only if such combinations result inchemically stable compounds. In addition, unless otherwise indicated,functional group radicals are independently selected.

The term “leaving group”, as used herein, has the definition known tothose of ordinary skill in the art (see, March, Advanced OrganicChemistry, 4^(th) Edition, John Wiley & Sons, pp. 352–357, 1992, hereinincorporated by reference). Examples of leaving groups include, withoutlimitation, halogens such as F, Cl, Br, and I, diazo, aryl- andalkyl-sulfonyloxy groups, and trifluoromethanesulfonyloxy.

The term “aliphatic” as used herein means straight-chain or branchedC₁–C₁₂ hydrocarbon chain that is completely saturated or that containsone or more units of unsaturation. The term “aliphatic” also includes amonocyclic C₃–C₈ hydrocarbon or bicyclic C₈–C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic (said cyclic hydrocarbon chains are alsoreferred to herein as “carbocycle” or “cycloalkyl”), that has a singlepoint of attachment to the rest of the molecule wherein any individualring in said bicyclic ring system has 3–7 members. For example, suitablealiphatic groups include, but are not limited to, linear or branchedalkyl, alkenyl, alkynyl groups and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl) or (cycloalkyl)alkenyl.

The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and“alkoxycarbonyl”, used alone or as part of a larger moiety includes bothstraight and branched chains containing one to twelve carbon atoms. Theterms “alkenyl” and “alkynyl” used alone or as part of a larger moietyshall include both straight and branched chains containing two to twelvecarbon atoms, wherein an alkenyl comprises at least one double bond andan alkynyl comprises at least one triple bond.

The term “chemically stable” or “chemically feasible and stable”, asused herein, refers to a compound structure that renders the compoundsufficiently stable to allow manufacture and administration to a mammalby methods known in the art. Typically, such compounds are stable attemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “haloalkyl”, “haloalkenyl”, and “haloalkoxy”, means alkyl,alkenyl, or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “heteroatom” means N, O, or S and shall include any oxidizedform of nitrogen and sulfur, and the quaternized form of any basicnitrogen.

The term “amine” or “amino” used alone or as part of a larger moiety,refers to a trivalent nitrogen, which may be primary or which may besubstituted with 1–2 aliphatic groups.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic carbocyclic ring systems having a total of fiveto fourteen members, where at least one ring in the system is aromaticand wherein each ring in the system contains 3 to 8 ring members. Theterm “aryl” may be used interchangeably with the term “aryl ring”.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinmeans non-aromatic, monocyclic, bicyclic, or tricyclic ring systemshaving five to fourteen ring members in which one or more of the ringmembers is a heteroatom, wherein each ring in the system contains 3 to 7ring members.

One having ordinary skill in the art will recognize that the maximumnumber of heteroatoms in a stable, chemically feasible heterocyclic orheteroaromatic ring is determined by the size of the ring, degree ofunsaturation, and valence of the heteroatoms. In general, a heterocyclicor heteroaromatic ring may have one to four heteroatoms so long as theheterocyclic or heteroaromatic ring is chemically feasible and stable.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to fourteen ringmembers, and wherein at least one ring in the system is aromatic, atleast one ring in the system contains one or more heteroatoms, and eachring in the system contains 3 to 7 ring members. The term “heteroaryl”may be used interchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroarylalkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Suitable substituents on theunsaturated carbon atom of an aryl, heteroaryl, aralkyl, orheteroaralkyl group are selected from halogen; haloalky; —CF₃; —R⁴;—OR⁴; —SR⁴; 1,2-methylenedioxy; 1,2-ethylenedioxy; protected OH (such asacyloxy); phenyl (Ph); Ph substituted with R⁴; —OPh; —OPh substitutedwith R⁴; —CH₂Ph; —CH₂Ph substituted with R⁴; —CH₂CH₂(Ph); —CH₂CH₂(Ph)substituted with R⁴; —NO₂; CN; N(R′)₂; —NR⁴C(O)R⁴; —NR⁴C(O)N(R⁴)₂;—NR⁴CO₂R⁴; —NR⁴NRC(O)R⁴; —NR⁴C(O)N(R⁴)₂; —NR⁴NR⁴C(O)R⁴;—NR⁴NR⁴C(O)N(R⁴)₂; —NR⁴NR⁴CO₂R⁴; —C(O)C(O)R⁴—C(O)CH₂C(O)R′; —CO₂R′;—C(O)R′; —C(O)N(R′)₂; —OC(O)N(R⁴)₂; —SO₂R′; —SO₂N(R′)₂; —S(O)R⁴;—NR⁴SO₂N(R′)₂; —NR⁴SO₂R⁴; —C(═S)N(R′)₂; —C(═NH)—N(R′)₂;—(CH₂)_(y)NHC(O)R⁴; —(CH₂)_(y)R⁴; —(CH₂)_(y)NHC(O)NHR⁴;—(CH₂)_(y)NHC(O)OR⁴; —(CH₂)_(y)NHS(O)R⁴; —(CH₂)_(y)NHSO₂R⁴; or—(CH₂)_(y)NHC(O)CH(V—R⁴)R⁴; wherein each R⁴ is independently selectedfrom hydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted5–6 membered heteroaryl or heterocyclic ring, phenyl (Ph), —O—Ph, —CH₂(Ph); wherein y is 0–6; and V is a linker group. When R⁴ is C₁₋₆aliphatic, it may be substituted with one or more substituents selectedfrom —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —S(O) (C₁₋₄aliphatic), —SO₂(C₁₋₄ aliphatic), halogen, —(C₁₋₄ aliphatic), —OH,—O—(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H, —CO₂(C₁₋₄ aliphatic), —O-(haloC₁₋₄ aliphatic), or -halo(C₁₋₄ aliphatic); wherein each C₁₋₄ aliphaticis unsubstituted.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers are comprised of —O—, —S—,—NR*—, —C(R*)₂—, —C(O), or an alkylidene chain. The alkylidene chain isa saturated or unsaturated, straight or branched, C₁₋₆ carbon chainwhich is optionally substituted, and wherein up to two non-adjacentsaturated carbons of the chain are optionally replaced by —C(O)—,—C(O)C(O)—, —C(O)NR*—, —C(O)NR*NR*—, NR*NR*—, —NR*C(O)—, —S—, —SO—,—SO₂—, —NR*—, —SO₂NR*—, or —NR*SO₂—; wherein R* is selected from hydogenor aliphatic. Optional substituents on the alkylidene chain are asdescribed below for an aliphatic group.

An aliphatic group or a non-aromatic heterocyclic ring may contain oneor more substituents. Suitable substituents on the saturated carbon ofan aliphatic group or of a non-aromatic heterocyclic ring are selectedfrom those listed above for the unsaturated carbon of an aryl orheteroaryl group and the following: ═O, ═S, ═NNHR⁵, ═NN(R⁵)₂, ═NR⁵,—OR⁵, ═NNHC(O)R⁵, ═NNHCO₂R⁵, ═NNHSO₂R⁵, or ═NR⁵, where each R⁵ isindependently selected from hydrogen or a optionally substituted C₁₋₆aliphatic. When R⁵ is C₁₋₆ aliphatic, it may be substituted with one ormore substituents selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄aliphatic)₂, halogen, —OH, —O—(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H,—CO₂(C₁₋₄ aliphatic), —O-(halo C₁₋₄ aliphatic), or (halo C₁₋₄aliphatic); wherein each C₁₋₄ aliphatic is unsubstituted.

Substituents on the nitrogen of a non-aromatic heterocyclic ring areselected from —R⁶, —N(R⁶)₂, —C(O)R⁶, —CO₂R⁶, —C(O)C(O)R⁶,—C(O)CH₂C(O)R⁶, —SO₂R⁶, —SO₂N(R⁶)₂, —C(═S)N(R′)₂, —C(═NH)—N(R′)₂, or—NRSO₂R; wherein each R⁶ is independently selected from hydrogen, anoptionally substituted C₁₋₆ aliphatic, optionally substituted phenyl(Ph), optionally substituted —O—Ph, optionally substituted —CH₂ (Ph), oran unsubstituted 5–6 membered heteroaryl or heterocyclic ring. When R⁶is a C₁₋₆ aliphatic group or a phenyl ring, it may be substituted withone or more substituents selected from —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, halogen, —(C₁₋₄ aliphatic), —OH, —O—(C₁₋₄aliphatic), —NO₂, —CN, —CO₂H, —CO₂(C₁₋₄ aliphatic), —O-halo(C₁₋₄aliphatic), or (halo C₁₋₄ aliphatic); wherein each C₁₋₄ aliphatic isunsubstituted.

Schemes 2–8 illustrate the application of the process of Scheme 1 to thesynthesis of pyridinyl aryl amine derivatives. These pyridinyl diarylamines synthesized according to the present invention may be furtherfunctionalized according to methods known to those of skill in the artin order to produce compounds that are potent inhibitors of p38 kinase.

wherein:

-   -   R³ is selected from C₁–C₆ aliphatic; aryl; and aryl substituted        with C₁–C₆ aliphatic, aryl, nitro, CN, CO₂R′, CO₂N(R′)₂, OR′,        NCO₂R′, NR′C(O)N(R′)₂, or OC(O)N(R′)₂;    -   provided that R³ is not t-butyl;    -   G₁, G₂, G₃, G₄, and G₅ are independently selected from hydrogen,        aliphatic, aryl, substituted aryl, nitro, CN, OR′, CO₂R′,        CO₂N(R′)₂, NR′CO₂R′, NR′C(O)N(R′)₂, OC(O)N(R′)₂, F, Cl, Br, I,        O-Ts, O-Ms, OSO₂R′, and OC(O)R′;    -   X is a leaving group;    -   Y is —C(O)—O-Z;    -   Z is selected from C₁–C₆ aliphatic, benzyl, Fmoc, —SO₂R′ or Q,        provided that Q is not substituted with X or alkyne;    -   wherein Q and R′ are as defined above.

The various steps illustrated in Scheme 2 may be described as follows:

Step 1: The starting material 21 is available by synthesis from2-chloronicotinic acid according to procedures known in the art (see,e.g., Scheme 3). The starting material 21 is coupled with a protectedaryl amine 22 (see, e.g., Scheme 3) in the presence of an alkali metalsalt such as cesium carbonate in a solvent such as NMP; or alternativelyin the presence of a catalyst such as palladium acetate, optionally aligand such as BINAP or dppe, and optionally a base such as potassiumphosphate in a compatible solvent such as toluene, MTBE, DME, or hexane,to give the protected coupling product of formula 23.

Step 2: The protected coupling product 23 is reacted with an acid suchas TFA in a suitable solvent such as methylene chloride,1,2-dichloroethane, or chlorobenzene, to give the compound of formula24.

Scheme 3a illustrates the synthesis of starting material 21 and Scheme3b exemplifies the further derivatization of deprotected couplingproduct 24 of Scheme 2.

wherein R³, G₁, G₂, G₃, G₄, and G₅ are as set forth in Scheme 2 above.

The various steps illustrated in Schemes 3a and 3b may be described asfollows:

Step A: Nicotinic acid derivative 31 may be activated by reacting itwith a chloroformate activating agent such as SOCl₂,phenylchloroformate, or p-nitrophenyl chloroformate, or a carbodiimideactivating agent such as CDI, DCC, or EDC in the presence of HOBt andN-hydroxysuccinimide in a polar aprotic solvent such as CH₂Cl₂,1,2-dichloroethane, DMF, or NMP, and heating. An alcohol of the formulaR³OH is then added to form compound 32.

Step B: Compound 32 is coupled with a boronic acid such as 33 in thepresence of a catalyst such as palladium acetate, a base such as sodiumcarbonate, potassium carbonate, lithium carbonate, cesium carbonate,potassium t-butoxide, sodium t-butoxide, or lithium t-butoxide in asolvent such as toluene, MTBE, DME, or hexane to give 34.

Step C: Coupled product 34 is then N-oxidized in the presence of areagent such as MCPBA, peracetic acid, or MMPP in a chlorinated solventsuch as CH₂Cl₂ or 1,2-dichloroethane to give 35.

Step D: N-oxide 35 is activated in the presence of a reagent such asPOCl₃, POBr₃, SOCl₂, SO₂Cl₂, or SOBr₂ to give 21.

Steps 1 and 2 are as set forth in Scheme 2 above.

Step E: The free amine of 24 is derivatized to form the correspondingurea by reaction with an activated carbonyl such as X₄C(O)X₅, wherein X₄and X₅ are each independently selected from Cl, Br, I, imidazole, O-Ph,p-nitrophenyloxy, substituted O-aryl, or a leaving group, and thenreacting the carbonyl with ammonium hydroxide in a solvent such astoluene, DME, or MTBE to form 36.

Step F: The ester functionality of 36 is reduced to the correspondingalcohol in the presence of a reducing agent such as DIBAL, LAH, superhydride, L-Selectide, LiBH₄, NaBH₃(anilide), Red-Al, or NaBH₄ in asolvent such as THF, DME, MTBE, MeOH, EtOH, IPA, t-BuOH, glyme, ordiglyme to form 37.

Step G: The alcohol of 37 may be further functionalized such as byactivation with X₄C(O)X₅, wherein X₄ and X₅ are as described in step Eabove, then reacting the carbonyl with OH(CH₂)₂NH₂ to form 38.

Although the processes of schemes 4–7 are illustrated using specificreagents and starting materials, it will be appreciated by one of skillin the art that suitable analogous reactants and starting materials maybe used to prepare analogous compounds.

Scheme 4 provides an example using the method of the instant inventionto produce a diaryl amine.

The various steps illustrated in Scheme 4 may be briefly described asfollows:

Step 1: 6-chloro-2-(4-fluorophenyl)-nicotinic acid methyl ester 41 isavailable by synthesis from 2-chloronicotinic acid (see, e.g., Scheme5). 41 is coupled with a protected aryl amine such asBoc-2,6-difluoroaniline 42 (see, e.g., Scheme 5) in the presence of analkali metal salt such as cesium carbonate and a solvent such as NMP; oralternatively in the presence of a catalyst such as palladium acetate,optionally a ligand such as BINAP, and optionally a base such aspotassium phosphate in a compatible solvent such as toluene to give theprotected coupling product of formula 43.

Step 2: Protected coupling product 43 is reacted with an acid such asTFA in a suitable solvent such as methylene chloride to give thecompound of formula 44.

More generally, one of skill in the art will recognize that the compoundof formula 44 may be produced by the reaction of 41a with 42a:

wherein X and Y are as set forth above.

Scheme 5a illustrates the synthesis of starting material 41 and Scheme5b illustrates the further derivatization of the deprotected couplingproduct 44 of Scheme 4.

The various steps illustrated in Schemes 5a and 5b may be brieflydescribed as follows:

Step A: 6-Chloronicotinic acid 51 is activated by reacting with achloroformate activating agent such as SOCl₂, phenylchloroformate, orp-nitrophenyl chloroformate, or a carbodiimide activating agent such asCDI, DCC, or EDC in the presence of HOBt and N-hydroxysuccinimide in apolar aprotic solvent such as CH₂Cl₂, 1,2-dichloroethane, DMF, or NMP,and heating. An alcohol such as methanol is then added to form6-chloronicotinic acid methyl ester 52.

Step B: Compound 52 is coupled with a boronic acid such as 53 in thepresence of a catalyst such as palladium acetate, a base such as sodiumcarbonate, potassium carbonate, lithium carbonate, cesium carbonate,potassium t-butoxide, sodium t-butoxide, or lithium t-butoxide in asolvent such as toluene, MTBE, DME, or hexane to give 54.

Step C: The coupled product 54 is then N-oxidized in the presence of areagent such as MCPBA, peracetic acid, or MMPP in a chlorinated solventsuch as CH₂Cl₂ or 1,2-dichloroethane to give 55.

Step D: The activated N-oxide 55 is halogenated in the presence of areagent such as POCl₃, POBr₃, SOCl₂, SO₂Cl₂, or SOBr₂ to give 41.

Steps 1 and 2 are as set forth for Scheme 4 above.

Step E: The free amine of 44 is derivatized to form the correspondingurea by reaction with an activated carbonyl such as X₄C(O)X₅, wherein X₄and X₅ each are independently selected from Cl, Br, I, imidazole, O-Ph,p-nitrophenyloxy, substituted O-aryl, or a leaving group, and thenreacting the carbonyl with ammonium hydroxide in a solvent such astoluene, DME, or MTBE to form 56.

Step F: The ester functionality of 56 is reduced to the correspondingalcohol in the presence of a reducing agent such as DIBAL, LAH, superhydride, L-Selectide, LiBH₄, NaBH₃(anilide), Red-Al, or NaBH₄ in asolvent such as THF, DME, MTBE, MeOH, EtOH, IPA, t-BuOH, glyme, ordiglyme to form 57.

Step G: The alcohol of 57 may be further functionalized such as byreaction with X₄C(O)X₅, wherein X₄ and X₅ are as described in step Eabove, then reacting the carbonyl with OH(CH₂)₂NH₂ to form 58.

Scheme 6 provides an example using the method of the instant inventionto produce a diaryl amine.

The various steps illustrated in Scheme 6 may be briefly described asfollows:

Step 1: 6-chloro-2-(2,4-difluorophenyl)-nicotinic acid ethyl ester 61 isavailable by synthesis from 2-chloronicotinic acid (see, e.g., Scheme7). 61 is coupled with a protected aryl amine such asBoc-2,6-difluoroaniline 42 (see, e.g., Scheme 7) in the presence of analkali metal salt such as cesium carbonate and a solvent such as NMP; oralternatively in the presence of a catalyst such as palladium acetate,optionally a ligand such as BINAP, and optionally a base such aspotassium phosphate in a compatible solvent such as toluene to give theprotected coupling product of formula 62.

Step 2: The protected coupling product 62 is reacted with an acid suchas TFA in a suitable solvent such as methylene chloride to give thecompound of formula 63.

More generally, one of skill in the art will recognize that the compoundof formula 63 may be produced by the reaction of 61a with 42a:

wherein X and Y are as defined above.

Scheme 7a illustrates the synthesis of starting material 61 and Scheme7b illustrates the further derivatization of the deprotected couplingproduct 63 of Scheme 6.

The various steps in Schemes 7a and 7b may be briefly described asfollows:

Step A: 6-Chloronicotinic acid 51 is activated by reacting with achloroformate activating agent such as SOCl₂, phenylchloroformate, orp-nitrophenyl chloroformate, or a carbodiimide activating agent such asCDI, DCC, or EDC in the presence of HOBt and N-hydroxysuccinimide in apolar aprotic solvent such as CH₂Cl₂, 1,2-dichloroethane, DMF, or NMP,and heating. An alcohol such as ethanol is then added to form6-chloronicotinic acid ethyl ester 71.

Step B: Compound 71 is coupled with a boronic acid such as 72 in thepresence of a catalyst such as palladium acetate, a base such as sodiumcarbonate, potassium carbonate, lithium carbonate, cesium carbonate,potassium t-butoxide, sodium t-butoxide, or lithium t-butoxide in asolvent such as toluene, MTBE, DME, or hexane to give 73.

Step C: Coupled product 73 is then N-oxidized in the presence of areagent such as MCPBA, peracetic acid, or MMPP in a chlorinated solventsuch as CH₂Cl₂ or 1,2-dichloroethane to give 74.

Step D: The activated N-oxide 74 is halogenated in the presence of areagent such as POCl₃, POBr₃, SOCl₂, SO₂Cl₂, or SOBr₂ to give 61.

Steps 1 and 2 are as set forth for Scheme 6 above.

Step E: The ester functionality of 63 is saponified in the presence of abase such as NaOH in a solvent such as THF, and then acidified in thepresence of an acid such as HCl to form 75.

Step F: 75 is then reacted with diphosgene followed by NH₄OH to form theamide-urea compound 76.

The various steps in Scheme 8 may be briefly described as follows:

Step A: 6-chloro-2-(2,4-difluorophenyl)-nicotinic acid ethyl ester 61 isavailable by synthesis from 2-chloronicotinic acid. Starting material 61is coupled with a protected aryl amine such as Boc-2,6-difluoroaniline42 in the presence of an alkali metal salt such as cesium carbonate in acompatible solvent such as NMP to give the protected coupling product.The protected coupling product is then reacted with an acid such as TFAin a suitable solvent such as methylene chloride to give the compound offormula 63.

Step B: The ester functionality of 63 is saponified in the presence of abase such as NaOH in a solvent such as THF, and then acidified in thepresence of an acid such as HCl to form 75.

Step C: 75 is then reacted with diphosgene followed by NH₄OH to form theamide-urea compound 76.

The following examples illustrate the present invention in a manner inwhich it may be practiced, but should not be construed as limitationsupon the overall scope of the processes of the invention.

Where applicable, the following HPLC method was utilized unlessotherwise indicated: a gradient of water:acetonitrile, 0.1% TFA(90:10→10:90→90:10) was run over 26 minutes at 1 mL/min and 254 nm. Themethod utilizes the Zorbax SB Phenyl 4.6×25 cm column, 5 μm. The term“T_(ret)” refers to the retention time, in minutes, associated with thecompound.

According to another embodiment, the methods of of the present inventionprovides compounds of formula (A) or formula (B):

wherein:

-   -   each of X₁, X₂, X₃, and X₄ is independently selected from fluoro        or chloro; and    -   R is H or methyl.

Compounds of formula (A) and formula (B) are useful as inhibitors ofp38. International PCT Publication WO 99/58502 (hereinafter “the '502publication”), the disclosure whereof is incorporated herein byreference, discloses a genus of compounds that encompasses compounds offormula (A) and formula (B). The methods of the present invention may bereadily used to produce compounds of the '502 publication.

According to a preferred embodiment of formula (A), each of X₁, X₂, X₃,and X₄ is fluoro. According to another preferred embodiment of formula(A), R is H.

According to a preferred embodiment of formula (B), each of X₁, X₂, andX₄ is fluoro. According to another preferred embodiment of formula (B),R is H.

According to the most preferred embodiment of formula (B), the methodsof the present invention produce compound 77 below:

EXAMPLES Example 1

2-Chloro-nicotinic acid methyl ester (52): 52 was prepared according tothe method of Synth. Comm. 26(12), 2257–2272 (1996). To a nitrogenpurged flask was charged 2-chloro-nicotinic acid (1000.0 g, 6.0 moles,1.0 eq) followed by 9 L methylene chloride. To this was added thionylchloride (1.4 L, 19.7 moles, 3.2 eq.) and the reaction was heated to 40°C. with vigorous stirring under nitrogen overnight. The acid chloridesolution was cooled in an ice bath and methanol (3 L, 74 moles, 12 eq.)was slowly added while keeping the temperature at 20° C. The ratelimiting parameter is the vigorous evolution of copious quantities ofHCl gas. After the addition, HPLC analysis [T_(ret) startingmaterial=7.5 min, T_(ret) 52=11 min] showed the product had formedimmediately. The volatiles were removed in vacuo and the residueextracted from 10% Na₂CO₃ with EtOAc. The combined organics were dried(MgSO₄), filtered, and concentrated to a pale yellow oil.

Example 2

2-(4-Fluoro-phenyl)-nicotinic acid methyl ester (54): To a nitrogenpurged flask was charged Pd(Ph₃)₄ (1.84 g, 1.6 mmoles, 0.005 eq), sodiumcarbonate (42.8 g, 404 mmoles, 1.3 eq), 52 (55.5 g, 320.6 mmoles, 1.0eq), p-fluorophenylboronic acid (53.8 g, 384.7 mmoles, 1.2 eq), followedby 1.3 L denatured EtOH. The reaction was heated to 78° C. with vigorousstirring under N₂ overnight. HPLC analysis [T_(ret) 52=10 min, T_(ret)54=12 min] of the reaction mixture showed that the starting material wascompletely consumed and a later-eluting peak produced. The reaction wascooled to room temperature and the solvents removed under vacuum. Theresidue was dissolved in EtOAc, washed, dried (MgSO₄), filtered throughcelite, and concentrated to afford a pale yellow solid 54.

Example 3

2-(4-Fluoro-phenyl)-1-oxy-nicotinic acid methyl ester (55): To anitrogen purged flask was charged urea hydrogen peroxide (86.9 g, 924mmoles, 4.0 eq.), the diaryl pyridine 54 (53.4 g, 231 mmoles, 1.0 eq)and 530 mL acetic acid. The bright yellow homogeneous solution washeated to 70–75° C. with vigorous stirring under nitrogen until the HPLCanalysis [T_(ret) 54=12 min, T_(ret) 55=10 min] showed >97% completion.The reaction was cooled to room temperature and the contents slowlypoured onto 500 g of ice. To the vigorously stirred icy mixture wasslowly added 6N NaOH to pH 7 while maintaining a temperature of 30° C.EtOAc and NaHCO₃ (solid) were added until an aqueous pH of 8–9 wasreached, and the solids dissolved. The layers were separated and theaqueous layer back-extracted with EtOAc. The combined organics werewashed with 5% NaHCO₃ and then tested by peroxide test strips for thepresence of oxidant. If the organic layer was positive for peracid, thebicarbonate washes were repeated until the test was negative. Oncenegative for peracid, the combined organics were dried (MgSO₄),filtered, and concentrated to a pale yellow solid 55.

Example 4

6-Chloro-2-(4-fluoro-phenyl)-nicotinic acid methyl ester (41): To anitrogen purged flask was charged the N-Oxide 55 (45 g, 182 mmoles, 1.0eq) followed by 300 mL dichloroethane. The phosphorous oxychloride (101mL, 1080 mmoles, 6 eq) was added all at once, causing an immediate risein temperature from 17 to 19° C. followed by gradual warming after that.The solution was heated under nitrogen to 70–75° C. until HPLC analysis[T_(ret) 55=10 min, T_(ret) 41=17 min] showed >94% completion. Thereaction was cooled to room temperature and the contents concentratedunder vacuum to remove most of the POCl₃. The remainder was quenched byslowly pouring onto 450 g of ice. After melting the ice, the product wasextracted into methylene chloride. The combined organics were dried(MgSO₄), filtered through silica, eluted with methylene chloride, andconcentrated to a solid 41.

Example 5

6-(2,6-Difluoro-phenylamino)-2-(4-fluoro-phenyl)-nicotinic acid methylester (44): To a nitrogen purged flask was charged palladium acetate(13.2 g, 59 mmoles, 0.04 eq), racemic BINAP (36.6 g, 59 mmoles, 0.04eq), followed by 1.9 L toluene. The heterogeneous slurry was heated to50° C. under nitrogen for 2 hours, cooled to 30° C., then the pyridylchloride 41 (386.4 g, 1.45 moles, 1.0 eq) and Boc-2,6-difluoroaniline 42(386.4 g, 1.69 moles, 1.2 eq), and K₃PO₄ (872 g, 4.1 moles, 2.8 eq) wereadded all at once followed by a 1.9 L toluene rinse. The heterogeneousreaction mixture was heated to 100° C. overnight and monitored by HPLC.When the reaction showed complete conversion to 43 by HPLC [T_(ret)41=17 min, T_(ret) 43=20.5 min, T_(ret) 44=17.6 min, monitored at 229nm] (usually between 18–20 hours) the reaction was cooled to roomtemperature and the contents diluted with 1.94 L EtOAc. To this wasadded 1×1.94 L of 6N HCl, and both layers were filtered through celite.The celite wet cake was rinsed with 2×1.9 L EtOAc. The layers wereseparated and the organic layer washed with 1×1.9 L of brine, dried(MgSO₄), filtered and concentrated to a brown, viscous oil. To removethe Boc-protecting group, the oil was dissolved in 1.94 L of methylenechloride and 388 mL TFA was added. The reaction was stirred overnight tofacilitate Boc removal. The volatiles were removed in vacuo, EtOAc (1.9L) and sufficient quantity of 1 or 6N NaOH was added until the pH was2–7. Then a sufficient quantity of 5% NaHCO₃ was added to bring the pHto 8–9. The organic layer was separated and washed with 1×5% NaHCO₃,dried (MgSO₄), filtered an concentrated to a brown oil/liquid. The crudeoil/liquid was azeodried twice with a sufficient quantity of toluene. Attimes the free base precipitated out resulting in a slurry. The residuewas dissolved in 500 mL toluene and 1.6 L 1N HCl/ether solution wasadded, which resulted in the solids crashing out. Heat was applied untilthe homogenized/solids broke up. If necessary, 200 mL of EtOAc can beadded to facilitate the break up. After cooling, the solid 44 wasisolated by vacuum filtration.

Example 6

6-1-(2,6-Difluoro-phenyl)-ureido]-2-(4-fluoro-phenyl)-nicotinic acidmethyl ester (56): To a nitrogen purged flask was charged the aminoester HCl salt of 44 (262 g, 0.67 mole, 1.0 eq), followed by 1.2 Ltoluene. To the heterogeneous mixture was added phosgene (1.4 L of 1.93M toluene solution, 2.7 moles, 4.0 eq) and the reaction was heated to50° C. under nitrogen overnight. The progress of the reaction to formthe —NC(O)Cl moiety was monitored by HPLC [T_(ret) 44=17.6 min, T_(ret)carbamoyl intermediate=19.7 min, T_(ret) 56=16.4 min, monitored at 229nm]. Once the nitrogen was completely reacted, the brown solution wascooled to approximately −52° C., and NH₄OH (0.84 L, 12.4 moles, 18.5 eq)was slowly added dropwise. As the addition neared completion a solidformed. The slurry was stirred with 1 L of water and collected by vacuumfiltration. The wet cake was washed with 1×390 mL toluene to remove lateeluting impurities.

Example 7

1-(2,6-Difluoro-phenyl)-1-[6-(4-fluoro-phenyl)-5-hydroxymethyl-pyridin-2-yl]-urea(57): To a nitrogen purged flask was charged the urea-ester 56 (10.0 g,24.92 mmol, 1.0 eq) followed by 10 mL THF. The mixture was cooled to0–5° C. To the cooled solution was added DIBAL-H/THF solution (149.5 mL,149.5 mmol, 6.0 eq) dropwise over 20–30 minutes. The mixture was stirredat 15–20° C. while the reaction progress was monitored by HPLC [T_(ret)56=16.4 min, T_(ret) 57=14.0 min, monitored at 229 nm]. The reactionmixture was quenched into cooled (5–10° C.) 15% aqueous H₂SO₄ (150 mL).After the quench was completed, the mixture was stirred for 10–15minutes. To the mixture was added TBME (150 mL). The mixture was heatedat 50° C. for 60 minutes. The mixture was cooled to ambient temperature,and the aqueous layer was removed. The organic layer was concentrated toabout 35 mL of residual volume. The dilution and concentration processwas then repeated. The residual mixture was cooled to 0–2° C., and heldat that temperature for 45 minutes. The off-white solid 57 was collectedby suction filtration using cold toluene (25 mL) as a rinse solvent. Thesolid was dried under vacuum at ambient temperature for 3–5 hours toafford 80% corrected yield.

Example 8

(2-Hydroxy-ethyl)-carbamic acid6-[1-(2,6-difluoro-phenyl)-ureido]-2-(4-fluoro-phenyl)-pyridin-3-ylmethyl ester (58): To a nitrogen purged flask was charged the benzylicalcohol 57 (7.1 g, 19.0 mmoles, 1.0 eq) and CDI (6.2 g, 38.0 mmoles, 2.0eq) followed by 71 mL THF. The solution was stirred at room temperaturefor 1–2 hours and then test-quenched into dry acetonitrile/excessethanolamine. If the activation was not complete, additional CDI can beadded until the test quench indicated complete conversion. Once thetest-quench showed complete conversion to 58, the reaction was quenchedby slowly adding 2.0 eq ethanolamine (0.64 mL, 38 mmoles). The reactionwas stirred at room temperature for 2 hours whereupon HPLC analysis[T_(ret) 57=14.2 min, T_(ret) 58=13.6 min, monitored at 229 nm]indicated complete conversion to 58. The THF was removed under vacuumand the residue dissolved in 71 mL ethyl acetate and washed with aqueousNH4Cl solution (2×71 mL) followed by brine (1×71 mL). The organic layerwas azeodried with EtOAc (2×71 mL). The residue was reconstituted with71 mL EtOAc, filtered, and re-concentrated. To the final residue wasadded 7.1 mL EtOAc and 63 mL of toluene then gently heated to 35–40° C.Upon cooling, a white solid formed which could be isolated by vacuumfiltration and washed with cold toluene.

Example 9

2-(2,4-Difluorophenyl)-6-(2,6-difluorophenylamino)-nicotinic acid ethylester (63): In a 1 L, 4-necked, round-bottomed flask equipped with anoverhead mechanical stirrer, heating mantle, reflux condenser, andthermocouple was charged 61 (50 g), Cs₂CO₃ (150 g) and 0.15 L of NMP.The solution was stirred vigorously and heated to 65° C. at which timeto the suspension was added a solution of 42 (60 g) in 0.10 L of NMPover 10 minutes. Heating at 65° C. for 18 hours, HPLC showed ˜85%conversion of 61 to the desired Boc adduct. At this time, thetemperature was increased to 75° C., and HPLC analysis after heating foran additional 18 hours showed ˜97% conversion of 61 to the desired Bocadduct 62 (not shown). The mixture was then cooled to 20 and poured inone portion into 2.0 L of water stirring in a 4-necked, 3 L,round-bottomed flask equipped with an overhead mechanical stirrer andthermocouple. The temperature of the water rose from 22° C. to 27° C. asa result of the addition of the NMP solution. The suspension was thencooled to 15° C. and the tan solid was collected by filtration, rinsedwith water and pulled dry on the filter for 2 hours.

In a 2 L, 4-necked, round-bottomed flask equipped with an overheadmechanical stirrer and thermocouple was charged the tan solid and 0.8 Lof CH₂Cl₂. To the stirred solution was added 70 mL of TFA in oneportion. After two hours stirring at ambient temperature, none of theBoc protected material was detected by HPLC, and the mixture wasconcentrated by rotary evaporation. The oily residue was taken up in 0.7L EtOAc, and treated with 0.7 L saturated NaHCO₃, during which gas wasproduced. The EtOAc layer was washed with 0.25 L saturated NaCl andconcentrated by rotary evaporation. To the resultant brown oil was added0.2 L EtOAc and the solution treated with HCl in Et₂O (0.4 L of 2.0 Msolution) and stirred for 60 minutes. The product 63, a yellow powder,was collected by filtration (70.5% yield).

The product may be recrystallized by heating the crude salt in 4 mLEtOH/g of crude product to reflux, then cooling to ambient temperature.

While we have hereinbefore presented a number of embodiments of thisinvention, it is apparent that the basic construction can be altered toprovide other embodiments which utilize the methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the claims appended hereto rather than the specificembodiments which have been presented hereinbefore by way of example.

1. A process for producing a diaryl amine compound of the formula (I):

or a salt thereof, said process comprising the steps of (1) coupling acompound of formula (II) with an amine of formula (III) in the presenceof an alkali metal salt or a transition metal catalyst:

 to form a compound of formula (IV):

 and (2) removing radical Y from the compound of formula (IV) in thepresence of an acid; wherein: Ar₁ and Ar₂ are independently Q; whereineach Q is an aryl or heteroaryl ring system optionally fused to asaturated or unsaturated 5–8 membered sing having 0–4 heteroatoms,wherein either Ar₁ or Ar₂, is a heteroaryl ring; wherein Q is optionallysubstituted at one or more ring atoms with one or more substituentsindependently selected from halo; C₁–C₆ aliphatic optionally substitutedwith N(R′)₂, OR′, CO₂R′, C(O)N(R′)₂, OC(O)N(R′)₂, NR′CO₂R′, NR′C(O)R′,SO₂N(R′)₂, N═CH—N(R′)₂, or OPO₃H₂; C₁–C₆ alkoxy optionally substitutedwith N(R′)₂, OR′, CO₂R′, C(O)N(R′)₂, OC(O)N(R′)₂, NR′CO₂R′, NR′C(O)R′,SO₂N(R′)₂, N═CH—N(R′)₂, or OPO₃H₂; Ar₃; CF₃; OCF₃; OR′; SR′; SO₂N(R′)₂;OSO₂R′; SCF₃; NO₂; CN; N(R′)₂; CO₂R′; CO₂N(R′)₂; C(O)N(R′)₂; NR′C(O)R′;NR′CO₂R′; NR′C(O)C(O)R′; NR′SO₂R′; OC(O)R′; NR′C(O)R²; NR′CO₂R²;NR′C(O)C(O)R²; NR′C(O)N(R′)₂; OC(O)N(R′)₂; NR′SO₂R²; NR′R²; N(R²)₂,OC(O)R²; OPO₃H₂; and N═CH—N(R′)₂; R′ is selected from hydrogen; C₁–C₆aliphatic; or a 5–6 membered carbocyclic or heterocyclic ring systemoptionally substituted with 1 to 3 substituents independently selectedfrom halo, C₁–C₆ alkoxy, cyano, nitro, amino, hydroxy, and C_(1–C) ₆aliphatic; R² is a C₁–C₆ aliphatic optionally substituted with N(R′)₂,OR′, CO₂R′, C(O)N(R′)₂or SO₂N(R′)₂; or a carbocyclic or heterocyclicring system optionally substituted with N(R′)₂, OR′, CO₂R′, C(O)N(R′)₂orSO₂N(R′)₂; wherein Ar₃ is an aryl or heteroaryl ring system optionallyfused to a saturated or unsaturated 5–8 membered ring having 0–4heteroatoms; wherein Ar₃ is optionally substituted at one or more ringatoms with one or more substituents independently selected from halo;C₁–C₆ aliphatic optionally substituted with N(R′)₂, OR′, CO₂R′,C(O)N(R′)₂, OC(O)N(R′)₂, NR′CO₂R′, NR′C(O)R′, SO₂N(R′)₂, N═C—N(R′)₂, orOPO₃H₂; C₁–C₆ alkoxy optionally substituted with N(R′)₂, OR′, CO₂R′,C(O)N(R′)₂, OC(O)N(R′)₂, SO₂N(R′)₂, NR′CO₂R, NR′C(O)R′, N═C—N(R′)₂, orOPO₃H₂; CF₃; OCF₃; OR′; SR′; SO₂N(R′)₂; OSO₂R′; SCF₃; NO₂; CN; N(R′)₂;CO₂R′; CO₂N(R′)₂; C(O)N(R′)₂; NR′C(O)R′; NR′CO₂R′; NR′C(O)C(O)R′;NR′SO₂R′; OC(O)R′; NR′C(O)R²; NR′CO₂R²; NR′C(O)C(O)R²; NR′C(O)N(R′)₂;OC(O)N(R′)₂; NR′SO₂R²; NR′R²; N(R²)₂; OC(O)R²; OPO₃H₂; and —N═C—N(R′)₂;X is a leaving group; Y is —C(O)—O-Z; and Z is C₁–C₆ aliphatic, benzyl,Fmoc, —SO₂R′or Q, provided that Q is not substituted with X or alkyne.2. The process according to claim 1, wherein the process is performedusing a transition metal catalyst.
 3. The process according to claim 2,wherein the transition metal catalyst comprises palladium.
 4. Theprocess according to claim 3 wherein the catalyst is PdL_(n), whereineach L is independently selected from —OAc, —O-tolyl, halogen, PPh₃,dppe, dppf, dba, and BINAP; and n is an integer from 0–4.
 5. The processaccording to claim 2, wherein the step of coupling a compound of formula(II) with an amine of formula (III) is performed in the presence of abase.
 6. The process according to claim 5, wherein the base is selectedfrom KOtBu, NaOtBu, K₃PO₄, Na₂CO₃, and Cs₂CO₃.
 7. The process accordingto claim 1, wherein the process is performed using an alkali metal salt.8. The process according to claim 7, wherein the alkali metal salt isselected from salts of potassium, rubidium, or cesium ions.
 9. Theprocess according to claim 8, wherein the alkali metal salt is selectedfrom potassium carbonate or cesium carbonate.
 10. The process accordingto claim 9, wherein the alkali metal salt is cesium carbonate.
 11. Theprocess according to claim 1, wherein X is selected from the groupconsisting of —Cl, —Br, —I. —F, —OTf, —OTs, iodonium, and diazo.
 12. Theprocess according to claim 1, wherein Y is Boc.
 13. The processaccording to claim 1 for producing a diaryl amine compound of theformula:

comprising the steps of (1) coupling a compound of formula 21 with anamine of formula 22 in the presence of an alkali metal salt or atransition metal catalyst, and (2) removing radical Y from the resultantcompound in the presence of an acid:

wherein: R₃ is selected from aliphatic, aryl, or aryl substituted withaliphatic, aryl, nitro, CN, CO₂R′, CO₂N(R′)₂, OR′, NCO₂R′,NR′C(O)N(R′)₂, and OC(O)N(R′)₂; provided that R₃ is not t-butyl; and G₁,G₂, G₃, G₄, and G₅ are independently selected from hydrogen, aliphatic,aryl, substituted aryl, nitro, CN, OR′, CO₂R′, CO₂N(R′)₂, NR′CO₂R′,NR′C(O)N(R′)₂, OC(O)N(R′)₂, F, Cl, Br, I, O-TOs, O-Ms. OSO₂R′, andOC(O)R′.
 14. The process according to claim 13, wherein the process isperformed using a transition metal catalyst.
 15. The process accordingto claim 14, wherein the transition metal catalyst comprises palladium.16. The process according to claim 15 wherein the catalyst is PdL_(n),wherein each L independently is selected from —OAc, —O-tolyl, halogen,PPh₃, dppe, dppf, dba, and BINAP; and n is an integer from 0–4.
 17. Theprocess according to claim 14, wherein the step of coupling a compoundof formula 21 with an amine of formula 22 is performed in the presenceof a base.
 18. The process according to claim 17, wherein the base isselected from KOtBu. NaOtBu, K₃PO₄, Na₂CO₃, and Cs₂CO₃.
 19. The processaccording to claim 13, wherein the process is performed using an alkalimetal salt.
 20. The process according to claim 19, wherein the alkalimetal salt is selected from salts of potassium, rubidium, or cesiumions.
 21. The process according to claim 20, wherein the alkali metalsalt is selected from potassium carbonate or cesium carbonate.
 22. Theprocess according to claim 21, wherein the alkali metal salt is cesiumcarbonate.
 23. The process according to claim 13, wherein X is selectedfrom the group consisting of —Cl, —Br, —I, —F, —OTf, —OTs, iodonium, anddiazo.
 24. The process according to claim 13, wherein Y is Boc.
 25. Theprocess according to claim 1 for producing a diaryl amine compound ofthe formula:

or a salt thereof, said process comprising the steps of (1) coupling acompound of formula 41a with an amine of formula 42a in the presence ofan alkali metal salt or a transition metal catalyst, and (2) removingradical Y from the resultant compound in the presence of an acid:


26. The process according to claim 25, wherein the process is performedusing a transition metal catalyst.
 27. The process according to claim26, wherein the transition metal catalyst comprises palladium.
 28. Theprocess according to claim 27 wherein the catalyst is PdL_(n), whereineach L is independently selected from —OAc, —O-tolyl, halogen, PPh₃,dppe, dppf, dba, and BINAP; and n is an integer from 0–4.
 29. Theprocess according to claim 26, wherein the step of coupling a compoundof formula 41a with an amine of formula 42a is performed in the presenceof a base.
 30. The process according to claim 29, wherein the base isselected from KOtBu, NaOtBu, K₃PO₄, Na₂CO₃, and Cs₂CO₃.
 31. The processaccording to claim 25, wherein the process is performed using an alkalimetal salt.
 32. The process according to claim 31, wherein the alkalimetal salt is selected from salts of potassium, rubidium, or cesiumions.
 33. The process according to claim 32, wherein the alkali metalsalt is selected from potassium carbonate or cesium carbonate.
 34. Theprocess according to claim 33, wherein the alkali metal salt is cesiumcarbonate.
 35. The process according to claim 25, wherein X is selectedfrom the group consisting of —Cl, —Br, —I, —F, —OTf, —OTs, iodonium, anddiazo.
 36. The process according to claim 25, wherein Y is Boc.
 37. Theprocess according to claim 1 for producing a diaryl amine compound ofthe formula:

or a salt thereof, said process comprising the steps of (1) coupling acompound of formula 61a with an amine of formula 42a in the presence ofan alkali metal salt or a transition metal catalyst, and (2) removingradical Y from the resultant compound in the presence of an acid:


38. The process according to claim 37, wherein the process is performedusing a transition metal catalyst.
 39. The process according to claim38, wherein the transition metal catalyst comprises palladium.
 40. Theprocess according to claim 39, wherein the catalyst is PdL_(n), whereineach L is independently selected from —OAc, —O-tolyl, halogen, PPh₃,dppe, dppf, dba, and BINAP; and a is as integer from 0–4.
 41. Theprocess according to claim 38, wherein the step of coupling a compoundof formula 61a with an amine of formula 42a is performed in the presenceof a base.
 42. The process according to claim 41, wherein the base isselected from KOtBu, NaOtBu, K₃PO₄, Na₂CO₃, and Cs₂CO₃.
 43. The processaccording to claim 37, wherein the process is performed using an alkalimetal salt.
 44. The process according to claim 43, wherein the alkalimetal salt is selected from salts of potassium, rubidium, or cesiumions.
 45. The process according to claim 44, wherein the alkali metalsalt is selected from potassium carbonate or cesium carbonate.
 46. Theprocess according to claim 45, wherein the alkali metal salt is cesiumcarbonate.
 47. The process according to claim 37, wherein X is selectedfrom the group consisting of —Cl, —Br, —I, —F, —OTf, —OTs, iodonium, anddiazo.
 48. The process according to claim 37, wherein Y is Boc.
 49. Theprocess according to claim 37 for producing a diaryl amine compound ofthe formula:

or a salt thereof, said process comprising the steps of (1) coupling acompound of formula 61 with an amine of formula 42 in the presence of analkali metal salt or a transition metal catalyst, and (2) removing theBoc group from the coupled amine in the presence of an acid:


50. The process according to claim 49 wherein the process is performedusing cesium carbonate.
 51. The process according to claim 49 furthercomprising the steps of: (a) reacting the compound of formula 63 with abase; and (b) acidifying the reaction mixture formed in step (a) toproduce a compound of the formula 75:


52. The process according to claim 51 wherein the base in step (a) isNaOH.
 53. The process according to claim 51 wherein the acid in step (b)is HCl.
 54. The process according to claim 51 further comprising thesteps of: (c) reacting the compound of formula 75 with diphosgene; and(d) treating the reaction mixture formed in step (c) with NH₄OH toproduce a compound of the formula 76:


55. The process according to claim 1, wherein the acid is selected fromthe group consisting of HCl, HBr, HI and an organic acid.
 56. Theprocess according to claim 13, wherein the acid is selected from thegroup consisting of HCl, HBr, HI and an organic acid.
 57. The processaccording to claim 25, wherein the acid is selected from the groupconsisting of HCl, HBr, HI and an organic acid.
 58. The processaccording to claim 37, wherein the acid is selected from the groupconsisting of HCl, HBr, HI and an organic acid.
 59. The processaccording to claim 49, wherein the acid is selected from the groupconsisting of HCl, HBr, HI and an organic acid.